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Engineered Fibrin Scaffolds for Cardiac Tissue Repair Kassandra S

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Engineered Fibrin Scaffolds for Cardiac Tissue Repair Kassandra S Engineered Fibrin Scaffolds for Cardiac Tissue Repair Kassandra S. Thomson A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2013 Reading Committee: Marta Scatena, Co-Chair Cecilia M. Giachelli, Co-Chair Michael Regnier Program Authorized to Offer Degree: Bioengineering Abstract Engineered Fibrin Scaffolds for Cardiac Tissue Repair Kassandra S. Thomson University of Washington, Department of Bioengineering Supervisory Committee: Dr. Michael Regnier, Bioengineering (Co-Chair) Dr. Marta Scatena, Bioengineering (Co-Chair) Dr. Cecilia M. Giachelli, Bioengineering Dr. Michael A. Laflamme, Pathology Dr. William M. Mahoney Jr., Pathology (GSR) Myocardial infarction (MI) causes significant cell loss and damage to myocardium. Cell-based therapies for treatment of MI aim to remuscularize the resultant scar, but the majority of transplanted cells do not survive or integrate with host tissue. Additionally, survival of tissue engineered constructs after implantation depends heavily on induction of a vascular response in host tissue in order to promote a quick anastomosis of the cellular graft. Scaffolds can improve cell retention following implantation, but often do little to enhance host-graft integration. Fibrin is an ideal biomaterial for cardiac tissue engineering as it is a natural, biodegradable polymer that can induce neovascularization, promote cell attachment, and has tunable mechanical properties. The research presented in this dissertation describes the development and characterization of a novel high density microtemplated fibrin scaffold with mechanical stiffness comparable to native myocardium, tunable degradation, and a microarchitecture designed to promote cellular organization within constructs. Acellular fibrin scaffolds demonstrated highly angiogenic properties when implanted. Cell seeding with a tri-cell mixture of cardiomyocytes, endothelial cells, and fibroblasts demonstrated the fibrin scaffolds promote cardiomyocyte alignment and the development of a pre-vascular network. The fibrin scaffolds are designed to promote graft cell organization and improve chances of construct survival and integration with host tissue upon implantation. Table of Contents List of Figures ………………………………………………………………………………………………………………………………………… iv List of Tables …………………………………………………………………………………………………………………………………………. vi Acknowledgements ……………………………………………………………………………………………………………………………… vii Dedication ……………………………………………………….………………………………………………………………………………….. viii Chapter 1: Background ……………………………………………………………………….……………………………………..…..……… 1 1.1. Significance……………………………………………………………………………………………….………………………..…….. 1 1.2. Cell-Based Therapies for MI….……………………………………………………………………………………………..……. 2 1.2.1. Cardiac Tissue Engineering …………………………………………………………….…..….……………..……… 3 1.2.2. Scaffold Material Considerations …………………………………………………………….………....………… 4 1.3. Wound Healing & the Foreign Body Response…………………………………………………....……………………. 5 1.3.1. Inflammation & Granulation Tissue Formation ………………………………………………………….…. 5 1.3.2. Foreign Body Response & Fibrous Capsule Formation …………………………….…………..………… 6 1.4. Vasculogenesis, Angiogenesis, & Vessel Maturation………………………………………………….…..……….… 7 1.4.1. Vasculogenesis ……………………………………………………………………………………….…………..…….…. 7 1.4.2. Angiogenesis ………………………………………………………………………………………………………………… 7 1.4.3. Vessel Maturation ………………………………………………………………………………………………………… 8 1.5. Vascularization of Tissue Engineering Constructs……………………………………………….…….………….…… 9 1.6. Fibrin as an Angiogenic Scaffold Material………………………………………………………….…………….………. 10 1.6.1. Fibrin Formation ……………………………………………………………………………….………………………… 10 1.6.2. Fibrinolysis ………………………………………………………………………………………….………….…………… 10 1.6.3. Fibrin as an Angiogenic Scaffold Material …………………………………………….…………….………. 11 1.7. Overall Hypothesis & Project Goals…………………………………………………………………………………………. 12 Chapter 2: Development, Modification, & Characterization of a Microchanneled & Microporous Fibrin Scaffold for Cardiac Tissue Engineering Applications …………………………………………………………….…..……….. 18 2.1. Introduction……………………………………………………………………………………………………………………………. 18 2.2. Materials & Methods…………………………………………………………………………………………………...…………. 21 2.2.1. Fibrin Scaffold Construction ……………………………………………………………………………...………… 21 2.2.2. Scaffold Modifications …………………………………………………………………………………..….………… 22 2.2.3. Architecture Evaluation ……………………………………………………………………………………….……… 22 2.2.4. Acellular Scaffold Myocardial Implants …………………………………………………………..……….…. 23 2.2.5. Histological Analysis ……………………………………………………………………………………………….…… 23 2.2.6. Mechanical Stiffness & in vitro Degradation Analysis ……………………………….…………..……. 24 2.2.7. Statistical Analysis …………………………………………………………………………………………….…….….. 24 2.3. Results…………………………………………………………………………………………………………………………..………… 25 2.3.1. Fibrin Scaffold Construction ………………………………………………………………………………..….…… 25 2.3.2. Acellular Scaffold Myocardial Implants …………………………………………………………….…….….. 25 2.3.3. Mechanical Stiffness & in vitro Degradation Analysis……………………………………………..….. 26 i 2.4. Discussion…………………………………………………………………………………………………………….…..…………….. 28 Chapter 3: Evaluation of Fibrin Scaffold Formulations for Promotion of Angiogenesis in a Subcutaneous Implant Model ……………………………………………………………………………………………………….……. 39 3.1. Introduction……………………………………………………………………………………………………………………………. 39 3.2. Materials & Methods……………………………………………………………………………………………….……………… 41 3.2.1. Fibrin Scaffold Construction ……………………………………………………………………………..……..….. 41 3.2.2. Scaffold Modifications ……………………………………………………………………….……….………………. 42 3.2.3. Acellular Scaffold Subcutaneous Implants ……………………………………………………..……………. 42 3.2.4. Sample Preparation & Histology ………………………………………………………………….……….…….. 43 3.2.5. Histological Analysis …………………………………………………………………………………….….…………. 43 3.2.6. Vascular Distribution Analysis ……………………………………………………………………….…….……… 44 3.2.7. Statistical Analysis……………………………………………………………………………….…………….……….. 45 3.3. Results…………………………………………………………………………………………………………………………..………… 45 3.3.1. Aprotinin Decreases Scaffold Degradation in vivo……………………………………….….………….. 45 3.3.2. Aprotinin Scaffolds Increase Angiogenic Response …………………………………………….….……. 46 3.3.3. Aprotinin Induces Vascular Infiltration of Scaffolds ………………………………………..…………… 47 3.3.4. Fibrous Capsule Thickness is Reduced by Aprotinin Scaffolds ………………………..…………….. 47 3.4. Discussion……………………………………………………………………………………………………………….………………. 48 Chapter 4: Optimization & Characterization of Cell-Seeding of Microtemplated Fibrin Scaffolds …..…. 59 4.1. Introduction……………………………………………………………………………………………………………………………. 59 4.2. Centrifugation Seeding Optimization…………………………………………………………………….…………..……. 61 4.2.1. Optimization of Scaffold Parameters …………………………………………………………….……….…… 61 4.2.2. Optimization of Cell Parameters ………………………………………………………………….……………… 62 4.2.3. Optimization of Seeding Protocol …………………………………………………………………….…..…….. 63 4.3. Materials & Methods………………………………………………………………………………………………………...……. 65 4.3.1. Fibrin Scaffold Construction ………………………………………………………………………………….….…. 65 4.3.2. Rat Cell Sources & Culture ……………………………………………………………………………………….….. 66 4.3.3. Human Cell Sources & Culture ………………………………………………………………………….…………. 66 4.3.4. Cell Pre-Treatments …………………………………………………………………..….……………………….…... 67 4.3.5. Cell Seeding & Culture of Fibrin Constructs ………………………………….…………….………………… 67 4.3.6. Live Imaging of Fluorescent Constructs ……………………………………………………………………….. 68 4.3.7. Sample Preparation, Histology & SEM ………………………………………………………………….…….. 68 4.3.8. Mechanical Stiffness Measurements of Cell-Seeded Constructs ………………………..…..……. 69 4.3.9. Statistical Analysis …………………………………………………………………………………………….….…….. 70 4.4. Results………………………………………………………………………………………………………………………...………….. 70 4.4.1. Static vs. Centrifugation Seeding …………………………………………………………………….………….. 70 4.4.2. Rat Tri-Cell Seeding …………………………………………………………………………..……………….……….. 70 4.4.3. Human Tri-Cell Seeding …………………………………………………………………………….….…………….. 71 4.4.4. Bi-Cell vs. Tri-Cell Seeding ………………………………………………………………………….……………….. 72 4.4.5. Mechanical Stiffness Measurements of Cell-Seeded Constructs ………………………..………… 72 ii 4.5. Discussion……………………………………………………………………………………………………………………….….…… 73 Chapter 5: Development of a Perfusion System for Improvement of Microtemplated Fibrin Scaffold Cell-Seeding …………………………………………………………………………………………………………………………….…………… 82 5.1. Introduction……………………………………………………………………………………………………………….…………… 82 5.2. Perfusion Seeding System Design………………………………………………………………………………..…….……. 85 5.2.1. Microtemplated Scaffold Void Fraction Estimation………………………………………..……….….. 85 5.2.2. Shear Stress Estimation of Flow Through Scaffolds ………………………………………………..……. 86 5.2.3. Perfusion Seeding System Considerations & Design Iterations …………………………….….….. 87 5.3. Materials & Methods……………………………………………………………………………………………………..……….. 89 5.3.1. Perfusion Seeding System Components & Assembly ……………………………………….…………… 89 5.3.2. Determination of Desirable Flow Rates ………………………………………………………………..……… 90 5.3.3. Fibrin Scaffold Construction ……………………………………………………………………………….….……. 90 5.3.4. Cell Culture ……………………………………………………………………………………………………………..….. 91 5.3.5. Perfusion Seeding of Microtemplated Scaffolds ………………………………….………….…….…….. 91 5.3.6. Assessment of Cell Viability & Perfusion-Seeded Scaffolds …………………………….………..….. 93 5.4. Results………………………………………………………………………………………………………………………….…………. 93 5.4.1. Determination of Optimal Seeding Duration ……………………………………………………..……….. 93 5.4.2. Determination of Optimal Cell Seeding Density ……………………………………………….……….….
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